Targeting Circadian Clock Proteostasis as a Novel Therapeutic Strategy in Tuberous Sclerosis Complex
Abstract
Scientific Objective and Rationale: The goal of this work is to identify novel approaches for treating tuberous sclerosis complex (TSC) by investigating the mechanistic basis of sleep and circadian rhythm dysfunction in mouse models. Among the most common complaints of patients with TSC and their families is sleep disturbance, yet sleep remains understudied and poorly understood in neurodevelopmental disorders. As a child neurologist, sleep scientist, and chronobiologist, I have devoted my work as a postdoctoral fellow in the Sahin laboratory and now my entire independent research group to understanding the mechanistic underpinnings of sleep and circadian rhythm disruption in neurodevelopmental disorders such as TSC. The circadian timekeeping system is the biological clock that synchronizes rhythms both within the tissues of an animal and between the animal and its environment with the oscillations of the earth. The mis-alignment of circadian clocks potently contributes to metabolic disease, cancer, seizure risk, and of course, sleep disruption. The integrity of the circadian system is therefore particularly important to individuals with TSC. Circadian rhythms are found throughout the kingdoms of life, and the mechanisms that regulate them are remarkably conserved in animal species. The laboratory mouse provides a reproducible and highly validated model for studying circadian rhythms in models of human disease. Using cellular and animal models for TSC, we have made two major findings: (1) Mouse models of TSC demonstrate abnormal circadian behavior and physiology. This results from abnormally high levels of the core circadian protein BMAL1 in TSC mutants. These elevated levels result from a combination of overproduction and reduced degradation. We found that when we reduced BMAL1 to physiological levels, we were able to fully reverse the circadian abnormalities. (2) The TSC/mTOR pathway biochemically regulates BMAL1, licensing its association with the machinery in cells that make new protein. This association promotes circadian oscillations in protein synthesis and is defective in Tsc2 mutant cells. Together, our work reveals a surprising degree of direct biochemical, functional, and physiological interactions between the biology underlying TSC and the circadian clock mechanism and nominates several key questions: (1) If modulation of BMAL1 levels rescues circadian phenotypes in TSC mouse models, what are the biochemical mechanisms that change BMAL1 stability in TSC mutant cells and animals? (2) What are the downstream genes and proteins regulated by BMAL1 in Tsc2 mutant cells? Can they be targeted? (3) Normalization of BMAL1 in TSC mutants reverses their circadian abnormalities. Can we use drugs that regulate BMAL1 stability to fix circadian abnormalities in TSC mutant mice? What about other abnormalities in these mice? Focus Area(s) and Unmet Need: By investigating how BMAL1 regulates the expression of genes and proteins downstream of TSC/mTOR signaling, we will gain a deeper knowledge of TSC signaling pathways. Many of these differentially regulated genes could represent novel clinical biomarkers. We will identify the biochemical mechanisms that mis-regulate BMAL1 stability in TSC mutant cells. Results of these experiments could lead to the testing of individual responses to individual variability in TSC phenotypes. Most available TSC therapies have focused on the suppression of mTOR with rapalogs; these drugs can have widespread and non-specific adverse effects, limiting their applicability to symptoms of TSC such as sleep disturbance. Our work addresses the unmet need of investigating mechanisms of sleep and circadian disturbance in TSC and identifying new potential therapies for specific symptoms. We predict that our experiments could lead to novel symptom-specific therapeutics for TSC. Applicability, Benefits and Risk: Caution is always required in applying what we learn in animal
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810194
Entities
People
- Jonathan O. Lipton
Organizations
- United States Army